Differential Recognition of Computationally Optimized H3 Hemagglutinin Influenza Vaccine Candidates by Human Antibodies

Abbadi, Nada; Nagashima, Kaito; Pena-Briseno, Alma; Ross, Ted M.; Mousa, Jarrod J.

doi:10.1128/jvi.00896-22

Cited by 3 publications

(3 citation statements)

References 44 publications

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“…This enhanced response corroborates the broad reactivity (against different H3N2 influenza strains) of the COBRA antigen and the functionality of the adjuvant system. The HAI titers observed herein agree with results previously described for J4 antigen immunization in mice and humans (8,71), which reinforces the promising future of COBRA-based vaccines. It is important to mention that the strains evaluated for HAI were constitutive strains used in the generation of COBRA J4; however, the older strain A/Hong Kong/1/68 H3N2 (HK/68) was not used.…”

Section: Discussionsupporting

confidence: 90%

“…To evaluate the potential for J4 to confer protection, mouse-adapted HK/68 virus was used to challenge vaccinated mice. Of note, HK/68 was not considered in the generation of J4 sequence (71). Nevertheless, COBRA HA has been previously evaluated against contemporary and future co-circulating isolates, resulting in the neutralization of these viruses (14 drift viruses and two viruses representing future strains) (72).…”

Section: Discussionmentioning

confidence: 99%

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Development of a broadly active influenza intranasal vaccine adjuvanted with self-assembled particles composed of mastoparan-7 and CpG

et al. 2023

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Currently licensed vaccine adjuvants offer limited mucosal immunity, which is needed to better combat respiratory infections such as influenza. Mast cells (MCs) are emerging as a target for a new class of mucosal vaccine adjuvants. Here, we developed and characterized a nanoparticulate adjuvant composed of an MC activator [mastoparan-7 (M7)] and a TLR ligand (CpG). This novel nanoparticle (NP) adjuvant was co-formulated with a computationally optimized broadly reactive antigen (COBRA) for hemagglutinin (HA), which is broadly reactive against influenza strains. M7 was combined at different ratios with CpG and tested for in vitro immune responses and cytotoxicity. We observed significantly higher cytokine production in dendritic cells and MCs with the lowest cytotoxicity at a charge-neutralizing ratio of nitrogen/phosphate = 1 for M7 and CpG. This combination formed spherical NPs approximately 200 nm in diameter with self-assembling capacity. Mice were vaccinated intranasally with COBRA HA and M7-CpG NPs in a prime–boost–boost schedule. Vaccinated mice had significantly higher antigen-specific antibody responses (IgG and IgA) in serum and mucosa compared with controls. Splenocytes from vaccinated mice had significantly increased cytokine production upon antigen recall and the presence of central and effector memory T cells in draining lymph nodes. Finally, co-immunization with NPs and COBRA HA induced influenza H3N2-specific HA inhibition antibody titers across multiple strains and partially protected mice from a challenge against an H3N2 virus. These results illustrate that the M7-CpG NP adjuvant combination can induce a protective immune response with a broadly reactive influenza antigen via mucosal vaccination.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Development of a broadly active influenza intranasal vaccine adjuvanted with self-assembled particles composed of mastoparan-7 and CpG

et al. 2023

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“…While these have demonstrated the effectiveness of COBRA HA in both naïve and pre-immune models 10,47 , more data is needed to ascertain how it translates to human populations with more diverse genetic backgrounds and complex exposure histories. Recent studies have provided encouraging hints on this front, however, identifying broadly reactive antibodies in human vaccine cohorts that are cross-reactive with COBRA HAs 19,48 . This suggests that COBRA HAs retain structural elements capable of recalling existing protective antibody responses, while potentially broadening the immune response against additional strains.…”

Section: Discussionmentioning

confidence: 99%

Structural insights into the broad protection against H1 influenza viruses by a computationally optimized hemagglutinin vaccine

et al. 2023

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Influenza virus poses an ongoing human health threat with pandemic potential. Due to mutations in circulating strains, formulating effective vaccines remains a challenge. The use of computationally optimized broadly reactive antigen (COBRA) hemagglutinin (HA) proteins is a promising vaccine strategy to protect against a wide range of current and future influenza viruses. Though effective in preclinical studies, the mechanistic basis driving the broad reactivity of COBRA proteins remains to be elucidated. Here, we report the crystal structure of the COBRA HA termed P1 and identify antigenic and glycosylation properties that contribute to its immunogenicity. We further report the cryo-EM structure of the P1-elicited broadly neutralizing antibody 1F8 bound to COBRA P1, revealing 1F8 to recognize an atypical receptor binding site epitope via an unexpected mode of binding.

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Structural basis for the broad antigenicity of the computationally optimized influenza hemagglutinin X6

Nagashima,

Dzimianski,

Yang

et al. 2024

Structure

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Differential Recognition of Computationally Optimized H3 Hemagglutinin Influenza Vaccine Candidates by Human Antibodies

Cited by 3 publications

References 44 publications

Development of a broadly active influenza intranasal vaccine adjuvanted with self-assembled particles composed of mastoparan-7 and CpG

Development of a broadly active influenza intranasal vaccine adjuvanted with self-assembled particles composed of mastoparan-7 and CpG

Structural insights into the broad protection against H1 influenza viruses by a computationally optimized hemagglutinin vaccine

Structural basis for the broad antigenicity of the computationally optimized influenza hemagglutinin X6

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